IRE1β negatively regulates IRE1α signaling in response to endoplasmic reticulum stress.

IRE1 beta is an ER stress sensor uniquely expressed in epithelial cells lining mucosal surfaces. Here, we show that intestinal epithelial cells expressing IRE1 beta have an attenuated unfolded protein response to ER stress. When modeled in HEK293 cells and with purified protein, IRE1 beta diminishes expression and inhibits signaling by the closely related stress sensor IRE1 alpha. IRE1 beta can assemble with and inhibit IRE1a to suppress stress-induced XBP1 splicing, a key mediator of the unfolded protein response. In comparison to IRE1 alpha, IRE1 beta has relatively weak XBP1 splicing activity, largely explained by a nonconserved amino acid in the kinase domain active site that impairs its phosphorylation and restricts oligomerization. This enables IRE1 beta to act as a dominant-negative suppressor of IRE1 alpha and affect how barrier epithelial cells manage the response to stress at the host-environment interface.